title: TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations.
abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of right ventricular free wall myocardium and life-threatening ventricular arrhythmias. A missense mutation, c.1073C>T (p.S358L) in the transmembrane protein 43 (TMEM43) gene, has been genetically identified to cause ARVC type 5 in a founder population from Newfoundland. It is unclear whether this mutation occurs in other populations outside of this founder population or if other variants of TMEM43 are associated with ARVC disease. We sought to identify non-Newfoundland individuals with TMEM43 variants among patient samples sent for genetic assessment for possible ARVC. Of 195 unrelated individuals with suspected ARVC, mutation of desmosomal proteins was seen in 28 and the p.S358L TMEM43 mutation in six. We identified a de novo p.S358L mutation in a non-Newfoundland patient and five separate rare TMEM43 (four novel) sequence variants in non-Newfoundland patients, each occurring in an evolutionarily conserved amino acid. TMEM43 mutations occur outside of the founder population of the island of Newfoundland where it was originally described. TMEM43 sequencing should be incorporated into clinical genetic testing for ARVC patients.
authors.affiliation: Division of Molecular Genetics, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.forename: Jon R
authors.initials: JR
authors.lastname: Skinner
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.forename: Deborah
authors.initials: D
authors.lastname: Terespolsky
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krahn
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hamilton
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000503:physiopathology; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D006352:Heart Ventricles / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D009523:Newfoundland and Labrador; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D008565:Membrane Proteins; C528696:TMEM43 protein, human